Circadian rhythms dominate a large array of physiological, biochemical and behavioral responses in most living organisms. The circadian clock is an intrinsic time-tracking system that enables the adaptation to environmental changes. Disruption of circadian rhythms has profound influence to human health and has been linked to depression, sleep disorders, coronary heart disease, metabolic disturbances, neurodegenerative diseases and cancer. Thereby, the molecular mechanisms governing the circadian clock constitute a very attractive hold for the understanding of the links to physiology and metabolism, representing potential tools for the development of therapeutic strategies. Remarkably, 10-15% of all mammalian transcripts undergo circadian fluctuations in their expression levels. Thus, genome-wide mechanisms must operate in order to insure such global transcriptional regulation. Our recent studies (Cell (2006) 125: 497-508;Nature (2007) 450, 1086-90;Cell (2008) in press) have established that CLOCK, a master regulator of circadian rhythms, directly acetylates histones and its partner BMAL1. CLOCK intrinsic HAT enzymatic activity demonstrates that control of chromatin remodeling constitutes a key regulatory step governing the circadian clock machinery. In a search for non-histone substrates of CLOCK, we have explored the possibility that nuclear receptors could be acetylated in a circadian manner. This possibility is supported by the presence of a putative NRID (nuclear receptor interaction domain) in CLOCK and by the intimate links that exist between circadian physiology and regulation of metabolism by some distinct nuclear receptors. Our preliminary studies have identified HNF-4 as a privileged CLOCK target. This proposal is centered on deciphering the molecular, functional and physiological significance of this event. HNF-4 is a nuclear receptor which controls liver metabolism and hepatocyte differentiation. Its activity may be modulated by the binding of fatty acid acyl-CoA thioesters and has been linked to the control of glucose metabolism and, indirectly, to xenobiotic metabolism. Thus, we have identified a molecular link that has multiple molecular and physiological implications and paves the way to a number of important in vitro and in vivo studies. We predict that these studies will provide novel and important insights into how circadian physiology and metabolism are controlled by epigenetic processes. PUBLIC HEALTH RELEVANCE: The circadian clock governs a large variety of our rhythmic physiology, including sleep-wake cycles, metabolism and hormonal levels. This proposal is aimed at deciphering the intimate mechanisms by which the circadian clock controls a key player in liver metabolism, the nuclear receptor HNF4. These studies will provide novel and important insights into how circadian physiology and metabolism are controlled by epigenetic processes.